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Opportunities for TB Prevention
in College Students
Jennifer Flood MD, MPH
Tuberculosis Control Branch
California Department of Public Health
June 3, 2016
Young adults with TB in U.S.
• 18 year old who
arrived from
Guatemala 3 years
previously
• Presents with fever
and cough to ER
• Bronchitis diagnosed
• Returned to ER with
massive hemoptysis
• 22 year old in U.S.
since college entry
• TB in lymph nodes
around his airway
• With treatment lymph
nodes may get larger
before resolving
Q. “Is there anything I
could have done to
prevent this from
happening?”2
Natural History of TB
Latent TB infection
(LTBI)
5%
Progression to
active TB
disease
“Reactivation”
Exposure to
infectious
TB
90%
Remain latently infected
5%
Develop “primary”
active TB disease
3
Not infected
Failure to Prevent TB
• 1 in 10 individuals who develop TB die
• TB disease is costly ($40K- $1 million)
• TB spreads through the air
4
Questions
• What is the frequency of TB disease and
latent TB infection in young adults?
• What strategies are most effective to
detect and treat TB infection?
• How can TB disease be rapidly identified
when it occurs in college settings?
5
TB Cases in the United States
1982–2015
CDC, Annual Report, 2015
Salinas, et al. MMWR, 2016
First increase in 23 yrs
7
How do TB Cases Occur in California?
9
13%Recent
Transmission
79.5%Reactivation
of remote infection
7.5%Importation
~2,000 TB Cases
Per Year
Overseas Screening Requirement
NO TB screening is required for the following groups:
Visitor/tourist
Student Work
Unauthorized (undocumented)
Required for:
Immigrant
Refugees
Permanent resident applicants
Asylees
Status adjusters
TB Disease in Persons
Ages 18-24 in United States, 2011
15
Cases Incidence
Total 878 2.8/100,000
US born 629 0.9/100,000
Foreign-born 249 19/100,000
TB Exposures on College
Campuses in U.S.
• ~ 900 TB cases in 18-24 year olds
Potential for ~1 TB exposure every day on a
college campus in US
Reason for presentation: TB Cases among Adults 18-24 years old in United States, 2011
Reason for TB evaluation
n (%)
TOTAL 878
TB Symptoms 671 (76%)
Contact investigation 57 (7%)
Targeted testing 48 (5%)
Occupational screen 23 (3%)
Immigrant medical exam 27 (3%)
Other (HCW, incidental lab result,
unknown)52 (6%)
TB Case Characteristics in Foreign-born Adults 18-24 years old, U.S., 2011
CharacteristicForeign-born
n %
Years in US at TB diagnosis
<2 years 288 45.8%
2 – 5 years 231 36.7%
> 5 years 110 17.5%
Location of Birth
Mexico 125 19.9
Guatemala 46 7.3
India 43 6.8
China 40 6.4
Philippines** 40 6.4
Vietnam 36 5.7
Other 299 47.5
Clinical Characteristics TB Case: Adults 18-24 years old, U.S., 2011
Characteristic N %
Infectiousness
Smear positive, culture positive 346 39%
Smear negative, culture positive 193 22%
Site of Disease
Extrapulmonary only 165 19%
Pulmonary only 616 70%
Both extrapulmonary and pulmonary95 11%
Abnormal chest radiograph 694 79%
Cavitary chest radiograph 278 32%
Latent TB Infection in
18-24 year olds, U.S. 2011
IGRA positive
US-born 1.3%
Foreign-born 8.7%
________________________________
Total 2.5%
~ 800,000 young adults
Source:
Estimated using NHANES and 2011 census data20
American College Health Association
• All incoming students should be screened for risk factors
for TB through a screening questionnaire
• Students with identifiable risks factors should be tested
• Treatment for LTBI should be recommended and
completion should be a high priority
ACHA Guidelines: Tuberculosis Screening and Targeted Testing of College and University Students,
April 2014
Barriers to TB Prevention
Patient
• Patient feels well
• Perception of risk: uncertain and not urgent
• Worried about medicine side effects
Provider
• Not considered important clinical problem
• Unclear who to test/treat
• Suboptimal tests/treatment options
23
Opportunities for TB Prevention
in College Setting
• Young healthy adults
• Student enrollment procedures may
facilitate screening
• Recent testing and treatment advances
(specific test, shorter treatment)
• Can be monitored through treatment
• Risk of TB spread in dorm and classroom
setting is a motivating factor
24
Part 1: Key Points
• Most TB cases in the U.S. are due to
reactivation of LTBI and are preventable
• TB disease continues to cause death
• TB disease disproportionately affects the
foreign-born
• Latent TB infection is nearly 10 X higher in
foreign-born
• Historical barriers have impeded LTBI treatment
adoption in many practice settings
25
What is Risk-based Testing?
• Only test patients who have “TB risk
factors”
• Treatment decisions routine:
“A decision to test is a decision to
treat”
CDC, MMWR, 2000 27
Why not Test Everyone?
• Testing populations with low prevalence
will result in many false-positive results
• Among low-risk U.S.-born patients:
Miramontes, PLOS One, 2015
Pai, Clin Micro Rev, 2014
Prevalence of
latent TB
infection
False-positive
rate
2.8% 46%
28
U.S. Preventive Services Task Force
Population
Adults who are at increased risk for tuberculosis:
• persons born in, or former residents of, countries with
increased tuberculosis prevalence
• persons who live in, or have lived in, high-risk congregate
settings (such as homeless shelters and correctional
facilities)March 2016. http://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-
statement144/latent-tuberculosis-infection-screening
Recommendation Grade
The USPSTF recommends screening for
latent tuberculosis infection (LTBI) in
populations that are at increased risk.
29
California Tuberculosis Risk Assessment
A tuberculosis (TB) screening tool for College and University Students
Check appropriate risk factor boxes below. LTBI testing is recommended if any of the 5 boxes below are checked.
o Foreign-born person from a country with an elevated TB prevalence All countries within Africa, Asia/Pacific, Eastern Europe (including Russia), Latin America (including Mexico)
Interferon Gamma Release Assay (IGRA) is preferred over Tuberculin Skin Test (TST) for foreign-born persons.
o Current or planned immunosuppressionHIV infection, organ transplant recipient, treated with TNF-alpha antagonist (e.g., infliximab, etanercept, others), steroids (equivalent of
prednisone ≥15 mg/day for ≥1 month) or other immunosuppressive medication
o Close contact to someone with infectious active TB disease at any time
o Volunteered, worked or lived in a healthcare, homeless or correctional facility
o Travel or residence of > 1 month in a country with an elevated TB prevalence All countries within Africa, Asia/Pacific, Eastern Europe (including Russia), Latin America (including Mexico)
If LTBI test result is positive and active TB disease is ruled out, LTBI treatment is recommended.
DRAFT
Tuberculin Skin Test (TST)
• Delayed-type hypersensitivity reaction
• How to read: – Measure induration (not
erythema) at 48-72 hrs
– Record millimeters
• Positive test:– ≥ 5mm for immunosuppressed
including HIV, recent contacts
– ≥ 10mm for all others with TB risk
31
Interferon-Gamma Release Assays
(IGRAs)• QuantiFERON®-TB Gold (QFT)
– Reported as positive, negative, or
indeterminate
• T-SPOT.TB (T-Spot)
– Reported as positive, borderline, negative, or
indeterminate
32
IGRA advantages
• Advantages over TST
– Not affected by BCG vaccination
– Not affected by most non-tuberculous
mycobacteria
– Interpretation is more objective
– No return visit needed for test interpretation
– Patients and providers may lack confidence in
TST results
CDC, MMWR, 2010 | Pai, Clin Micro Rev, 2014 33
TST and QFT Specificity
Specificity95%
confidence
interval
TST without
BCG97 95–99
TST with BCG 59 46–73
QFT 96 94–98
Menzies, Ann Intern Med, 2007
Pai, Ann Intern Med, 2008 34
Testing Foreign-Born Patients
• Using a test with poor specificity will result in
many false-positive results
• Among foreign-born patients with prevalence 16%:
Pai, Clin Micro Rev, 2014
Miramontes, PLOS One, 2015
Test False-positive
rate
QFT 12%
TST 73%
35
Diagnosing Latent TB Infection
• TSTs and IGRAs cannot distinguish between
latent TB infection and active TB disease
• Active TB disease must be evaluated if
IGRA or TST is positive
Positive
TST or IGRA
Latent TB
infection
Active TB
disease
? ?
36
Rule out Active Disease Before
Starting LTBI Treatment!
• Symptom screen + chest radiograph
• If abnormal collect sputum:
1.AFB smear and culture
2.TB PCR/NAAT
• If sputum collected:
– Either start empiric treatment for active
disease
– Or await final culture results before starting
LTBI Rx 37
Part 2: Key Points
• Either IGRA or TST can aid in the
diagnosis of latent TB infection
• Neither test can distinguish between latent
TB infection and active TB disease
• IGRAs have advantages over TST in
foreign-born (BCG vaccinated)
38
Treatment Regimens for
Latent TB Infection
Medication(s) Frequency Duration Doses
Isonizaid (INH) Daily6–9
months180 - 270
Rifampin Daily 4 months(vs 3months)
120
Rifapentine
(RPT) + INHWeekly 3 months 12
40
Isoniazid (INH)
• Advantages
– Longstanding treatment for latent TB infection
– Efficacy is 60%–90%, depending on duration of
treatment
– Fewer drug-drug interactions
• Disadvantages
– Adherence
• Initiation and completion rates <50%
– Hepatotoxicity
• Incidence 0.1%, but increases with age
– Clinic time required for 9 monthly visits
Nolan, JAMA, 1999 | Smieja, Cochrane Database Syst Rev, 2000 | Menzies, Ann Int Med, 200841
Rifampin
• Advantages:
– Less hepatotoxicity (~5x less than INH)
– Greater adherence (78% RIF vs. 60% INH)
• Disadvantages:
– Less evidence of efficacy
– Multiple drug interactions
• Warfarin, oral contraceptives, methadone,
protease inhibitors
Hong Kong Chest Service/Tuberculosis Research Centre, Am Rev Respir Dis, 1992
Villarino, Am J Respir Crit Care Med, 1997 | Menzies, Ann Intern Med, 2008 42
Sterling, NEJM, 2011
INH-RPT INH
No. of
patients3,986 3,745
Frequency Weekly Daily
Duration 3 months 9 months
Administrati
onDirectly-observed Self-administered
43
Prevent TB Study Results
INH-RPT INH P-value
Effectiveness 1.9 per 1,000 4.3 per 1,000Non-
inferior
Completion 82.1% 69.0% P<0.001
Hepatotoxicity 0.4% 2.7% P<0.001
Sterling, NEJM, 2011 44
INH-RPT
• Advantages:
– Less hepatotoxicity (~ 7x less than INH)
– Greater adherence (82% INH-RPT vs. 69%
INH)
• Disadvantages:
– Multiple drug interactions
– Pill burden
– Flu-like / hypersensitivity syndrome (2.2%)
Bliven-Sizemore, Int J Tuberc Lung Dis, 2015
Sterling, Clin Infect Dis, 201545
Part 3: Key Points
• INH has been front line drug, but has low
treatment initiation and completion rates
• Short course regimens now preferred
given higher completion rates and lower
hepatotoxity
• INH-RPT (12 doses) is as efficacious as
INH (9 months)
46
Clinical Presentation:
Signs and Symptoms
Cough (dry/productive sputum) 75-80%
Weight loss 45-75%
Fatigue 60-70%
Fever 50-60%
Night sweats 50-55%
Hemoptysis 25-35%
Pleuritic chest pain
No symptoms 10-20%
Barnes 1988, Miller 2000
48
Radiographic Patterns of
Pulmonary TB
Pattern
Infiltrate Majority of Cases (80%)
85% upper
Cavitation Minority of Cases (20%)Rare in children and
primary TB
Adenopathy Uncommon
More common in children
and primary TB
Effusion May be present
49
Sputum AFB smear
• Smear positive ≥ 104 bacilli per ml
• Smear AFB amount correlates with infectiousness
• 40-60% of culture positive cases will be smear negative
Three smear negative specimens
does not “rule out” TB!
50
What is the Added Value of NAAT?
• For AFB smear (–):
– 50-70% of smear –/culture + cases will be + by
NAAT start treatment (earlier)
– If NAAT (–), the likelihood of TB lower• Release from isolation earlier (2 Xpert results finds all smear +)
• Still start treatment if suspicion is high
• For AFB smear (+):
– NAAT can confirm TB quickly
– If NAAT negative, prevent falsely diagnosing TB(likely NTM if inhibitors are ruled out and result repeated)
Luetkemeyer Clin Infect Dis 2016 51
Xpert MTB/RIF Test Performance
Compared with Culture, U.S. Patients
Sensitivity Specificity
1 Xpert 2 Xperts
Smear (+) 96.7%(59/61)
100%(62/62)
99.2%Smear (–) 59.3%
(16/27)
71.4%(20/28)
Luetkemeyer Clin Infect Dis 2016 52
Use of NAATs!
• NAAT should be used unless results
would not impact clinical or public health
management
• Xpert results showing Rif resistance
should:
– Be confirmed using sequencing and/or culture
– Trigger suspicion for MDR TB (not Rif
monoR)
CDC MMWR October 18, 2013 / 62(41);821-82453
Part 4: Key Points
• Most but not all patients have TB
symptoms
• Most patients do not have a cavity on CXR
• Use NAATs
• Clinical suspicion is crucial don’t be
afraid of empiric TB treatment
• Discuss with state/local TB control
program
54
Summary
• Most TB cases in the U.S. are preventable
• TB disease persists as a cause of
preventable morbidity and mortality
• College students should have risk-base
testing and treated if positive
• Foreign birth/travel, immunosuppressed,
TB contact are the main risks for TB
55
Summary
• Both IGRAs or TSTs can be used to
support the diagnosis of latent TB infection
• Neither test can distinguish between latent
TB infection and active TB disease
• IGRAs have advantages over TST in
foreign-born (BCG vaccinated)
56
Summary: How to treat?
• Short course regimens have higher
completion rates and are less hepatotoxic
• INH has very low treatment completion
rates
• INH-RPT (3 months) is as efficacious as
INH (9 months)
57
TB Elimination is achievable
• New tools can help simplify and improve
management of latent TB infection
1. Simple TB risk assessment
2. IGRAs
3. Short course regimens
58